PURPOSE: CKD-516 is a benzophenone analog with a modification of the B ring, which is replaced by a carbonyl group. The aim of this study is to assess the antivascular effects and the inhibition of cell proliferation of CKD-516.

MATERIALS AND METHODS: To assess the effect of CKD-516 on vascularization, we analyzed the effect on endothelial cells (HUVECs). To determine the inhibition of cell proliferation of CKD-516, we used a lung carcinoma cell line (H460). The alteration of microtubule analyzed using immunoblot, RT-PCR and confocal image. To evaluate the anti-tumor effects of gemcitabine and/or CKD-516, H460 xenograft mice were treated with CKD-516 (2.5 mg/kg) or gemcitabine (40 mg/kg) or CKD-516 + gemcitabine, and tumor growth was compared with vehicle-treated control. For histologic analysis, liver, spleen and tumor tissues were taken at 12 and 24 hours after CKD-516 injection from H460 xenograft mice.

RESULTS: We determined that cytoskeletal changes of HUVECs treated with 10 nM CKD-516 were assessed by immunoblot and confocal imaging. CKD-516 disrupts tubulin assembly and results in microtubule dysfunction inducing cell cycle arrest (G2/M). CKD-516 markedly enhanced the depolymerization of microtubules which may be related to vascular disrupting properties of CKD-516. Interestingly, CKD-516 decreased amount of total tubulin protein in HUVECs. Especially, CKD-516 decreased mRNA expression α-tubulin (HUVECs only) and β-tubulin (HUVECs and H460) at early time point (4 h). Immunocytochemical analysis showed that CKD-516 changed the cellular microtubule network and inhibited the formation of polymerized microtubules. We also showed extensive central necrosis of tumor by 24 h after treated with CKD-516 (2.5 mg/kg, i.p.). In H460 xenograft, CKD-516 combined with gemcitabine significantly delayed tumor growth as compared to control and gemcitabine alone.

CONCLUSION: These results suggest that CKD-516 is a novel agent with vascular disrupting properties, and enhances anti-tumor activity in combination with chemotherapy.

Citation Format: Young Joo Min, Chang Hoon Moon, Seung Ju Lee, Sang Ryun Ryu, Wha Ja Cho, Nal Ae Yoon, Sungchan Park, HeeJeong Cha. CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4498. doi:10.1158/1538-7445.AM2013-4498